The fusion of sperm and egg lead to the combination of the father's and mother's genetic information to create a new individual. In humans, as in all mammals, sperm must reach the egg, penetrate its protective coat, fuse with the oocyte membrane, and deliver its genetic material. Ion channels in the sperm mediate many of these steps, but most of these ion channels are also present in other tissues, including brain and heart. We have identified a class of ion channels, called CatSpers (Cation channel of Sperm) that are in mature sperm but not in any other tissues of the body, including developing organs. CatSpers are six transmembrane-spanning ion channel proteins localized primarily to the tail of mature sperm (Ren et al., 2001). CatSper1, the first of these ion channels to be identified, triggers calcium influx into the principal piece of the sperm tail. Calcium is required for sperm motility, and sperm from mice genetically engineered to lack the functional CatSper1 gene show a significant reduction in motility. Male mice homozygous for null-mutations in the CatSper1 gene are infertile (100%), but otherwise are completely normal. Another related sperm-specific protein, CatSper2, is also localized to its tail. Since these ion channels are only in mature sperm and required for fertility, a specific agent that blocks channel function should prevent fertilization. Experiments are proposed that will enable the expression of these novel genes in heterologous cell lines suitable for large-scale screening for small molecule blockers. This will provide a viable assay for screening for male contraceptive agents.